The focus of Project 2 will be to better understand the role of microglial cells in the generation and progression of neurodegenerative change in the human brain. These cells are a vital driving component of the cytokine cycle that forms the core of this research program. We hypothesize that microglial activation plays a central role on the development and progression of pathology in common neurodegenerative disorders such as Alzheimer's and Parkinson's disease (AD and PD) and that the extent of the microglial reaction is modulated by a number of different factors including the genotype of the individual and the local tissue environment. To achieve this objective we will study the microglial reaction in a number of unique human tissue cohorts at the transcriptomic, protein, and tissue morphology level. In Aim 1 we will compare and contrast microglial and inflammatory gene expression levels in cases of AD, PD, Parkinsonian dementia and dementia with Lewy bodies (DLB) using microarray techniques. Included in the analysis of AD cases will be post-mortem tissue from 9 patients treated with Ap as part of the Elan 102 trial. Genes with significantly altered expression will then be further investigated in the tissue using immunocytochemistry. In Aim 2 we will continue our investigations of the effect of ApoE gene polymorphisms on the extent of microglial pathology by studying the CFAS cohort, a large UK cohort of 450 unselected elderly individuals who have been followed in the community and for whom detailed prospective clinical and pathological data are available. By using a panel of microglial antibodies we will generate phenotypic profiles of microglia in the different degenerative disorders. In addition we will continue our investigations of the apparent differential response of grey and white matter microglial populations after severe head injury. Successful completion of these aims in conjunction with Core B and Project 3, will provide valuable information about the role of microglia in these neurodegenerative conditions, the effect of ApoE genotype on the pathology seen and the effects of the local tissue environment on the activation of microglia.